The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. We have synthesized the first selective A3 adenosine receptor agonists and antagonists. Recently this project has focused on the effects of adenosine agonists and antagonists in the central nervous system and on the possibility of therapeutics for treating neurodegenerative and cardiovascular diseases. An A3 agonist, administered chronically, proved to be highly cerebro-protective in an ischemic model in gerbils. A3 agonists cause morpholigical and biochemical changes in astroglial cells. Adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart. We have shown that synthetic adenosine agonists, selective for either the A1 or A3 subtype, protect ischemic cardiac myocytes in culture and thus might be beneficial to the survival of the ischemic heart. An acutely administered A3 agonist, Cl-IB-MECA, was cardioprotective in cell culture, through the selective activation of A3 receptors. The protection was blocked in the presence of a selective A3 receptor antagonist. In summary, highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well. It is proposed that modulation of A2B and A3 receptors may be useful in treating asthma and inflammatory diseases. The pharmacolgical properties of novel xanthines developed in our lab that act as selective A2B receptor antagonists are being explored. Since the three major subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the receptor protein, based on sequence analyses and computerized ene